Curriculum in CardiologyCurrent therapeutics and practical management strategies for pulmonary arterial hypertension
Section snippets
The value of invasive testing—hemodynamic assessment for diagnosis
In all patients suspected of having PAH, defined hemodynamically as a resting mean pulmonary artery pressure (mPAP) ≥25 mm Hg with a pulmonary capillary wedge pressure ≤15 mm Hg and PVR >3 Wood units, right side of the heart catheterization (RHC) is a critical first step and the current diagnostic standard for accurate hemodynamic assessment.6 Its purposes are multifactorial: to exclude left side of the heart disease (LHD) and pulmonary venous hypertension as a cause for PH, to determine a
The value of noninvasive assessment—imaging the right ventricle and other prognostic features
The value of echocardiography for experienced clinicians is not ensconced in the estimated PA pressures but rather in the assessment of the often underrepresented right ventricle and its impairment of cardiac performance. With increasing recognition of the importance of RV in PH, efforts have been directed toward understanding RV remodeling and mechanisms of RV adaptation using imaging techniques, with an appropriate and long-overdue emphasis on echocardiographic standardization of measures of
Acute vasodilator testing
All patients with PAH are recommended to undergo vasodilator testing with short-acting vasodilators such as adenosine, intravenous (IV) epoprostenol, or inhaled nitric oxide (NO) on initial RHC. The intention is to identify patients with pulmonary vasoreactivity, defined as a reduction in mPAP of at least ≥10 mm Hg to an absolute mPAP <35 to 40 mm Hg with either no change or an increase in CO.6 A very small subset of patients, <10%, demonstrates positive vasoreactivity and derives significant
Adjuvant long-term treatment measures
The evidence supporting use of these treatment measures in PAH is limited and based on uncontrolled clinical studies in PAH. Diuretic use is common in PAH and affords symptomatic benefit in these patients who often exhibit significant tricuspid regurgitation, RV volume overload with systemic venous congestion, and increased RV wall stress. Many of the clinical trials in PAH show that 50% to 70% of patients are taking diuretics at time of study.20 Digoxin, as shown from prior animal studies in
Prostacyclin therapies
Until the 1990s, the only therapies available for PAH included CCBs and anticoagulation.18, 23 Figure 2 illustrates the timeframe of FDA drug approval in the years after and summarizes current therapeutic options. As greater knowledge of the pathophysiology in PAH has emerged, 3 major pathways have been identified in the development and progression of PAH, each of which provide a therapeutic target for disease treatment: the prostacyclin, NO, and endothelin pathways (Figure 3).
The
Epoprostenol
The emergence of continuous IV epoprostenol as the first FDA-approved therapy for PAH transformed the field of PH. Epoprostenol remains the first-line preferred treatment for World Health Organization Functional Class (FC) IV patients and often serves as rescue therapy. Long-term use of epoprostenol improves hemodynamics and quality of life, delays lung transplantation in subjects with severe disease at presentation, and is the only advanced PH therapy prospectively proven to enhance survival.25
Practical management considerations
Treatment with epoprostenol should be initiated by experienced physicians at designated centers because of limitations in drug pharmacology. Epoprostenol, like endogenous prostacyclin, is a chemically unstable compound with a plasma half-life of <3 to 5 minutes. Because of peripheral vein irritation, long-term epoprostenol therapy is administered as a continuous IV infusion and requires a surgically implanted central venous catheter and portable infusion pump. Patients are required to learn the
Trepostinil
Trepostinil is a tricyclic benzene prostacyclin analog with similar pharmacologic action to epoprostenol that, by virtue of its longer elimination half-life, pH neutrality, and stability at room temperature, may be delivered by either subcutaneous (SC) (half-life 4.6 hours) or IV infusion (half life 4.4 hours) routes.33 Its longer half-life minimizes the risk of cardiovascular collapse with inadvertent interruption of infusion. Subcutaneous trepostinil was first approved in 2002 for the
Practical management considerations
Optimal dosing for trepostinil is not clear, as the mean effective doses in clinical trials of both SC and IV trepostinil have been highly variable and encompass a large range. Current practice patterns generally prefer doses of 50 to 100 ng/kg per minute, approximately 1.5 to 6 times greater than the epoprostenol dose.35 In contrast to IV epoprostenol, cassettes of IV trepostinil may be changed every other day rather than daily. Patients can transition from SC trepostinil to IV trepostinil
Iloprost
Direct dilatation of the pulmonary vasculature by inhalation is a potential therapeutic option, as it allows for more intrapulmonary selectivity, avoidance of right-to-left shunt blood flow, and naturally less systemic side effects. The first inhaled prostanoid, iloprost, was approved in 2004 after demonstrating efficacy and improved 6MWD both as a monotherapy in FC III and IV PAH and in inoperable chronic thromboembolic PH (CTEPH)37 and as combination therapy with bosentan.38 Comparative
Practical management considerations
Iloprost is administered via a dedicated nebulizer and has a short half-life, requiring frequent inhalation (up to 6-9 times daily) to achieve clinical effect. Similar to inhaled trepostinil, cough is the most common side effect reported. Patients who are not eligible for IV prostacyclin therapy may be advised to attempt inhaled iloprost, although frequent dosing poses a potential limitation with a propensity for noncompliance.
Endothelin receptor antagonists
Endothelin-1 (ET-1), the predominant cardiovascular endothelin isoform, is a potent vasoconstrictor that promotes PA smooth muscle cell proliferation and contributes to disease progression. Circulating plasma ET-1 levels are increased in PAH, and these levels correlate with PVR in the IPAH subgroup.39, 40 Endothelin-1 largely binds to 2 receptors, endothelin-A (ETA) and endothelin-B (ETB) receptors. Endothelin-A receptors, found on smooth muscle cells only, induce vasoconstriction and cellular
Bosentan
Bosentan, a widely-used nonselective ERA, received FDA approval in 2001 for patients with PAH with FC III or IV after the results of 2 randomized, double-blind, placebo-controlled trials.41, 42 In both studies, including the larger follow-up study, the BREATHE-1, bosentan first at a dose of 62.5 mg twice daily followed by 125 or 250 mg twice daily led to a statistically significant increase in the placebo-corrected 6MWD after 16 weeks. BREATHE-1 also assessed time to clinical worsening, that
Practical management considerations
The major toxicity associated with bosentan is hepatocellular injury by induction of the Cytochrome P2C9 (CYP2C9) P450 enzyme in the liver, requiring that patients be followed up with monthly liver function tests per the FDA. In the BREATHE-1 trial, patients taking 125 and 250 mg of bosentan twice daily had a dose-dependent increase in aminotransferase elevations, up to 8 times above the upper limit of normal.42 Consequently, bosentan is only approved as a 125-mg twice-daily dose by the FDA. It
Ambrisentan
Ambrisentan is a selective ERA with a ratio of ETA to ETB receptor selectivity of 77:1.46 Ambrisentan at a dose of 5 mg daily received FDA approval in 2007 for patients with FC II and III PAH. Two phase III trials of ambrisentan in PAH, ARIES-1 and ARIES-2, have been completed to date,47 and an improvement in 6MWD was realized in both studies.
Practical management considerations
Given the lower risk of aminotransferase elevation with ambrisentan (incidence of 3%, similar to patients not taking ERAs), ambrisentan treatment offers utility for patients in whom bosentan was not tolerated because of liver abnormalities.48 No significant pharmacokinetic interactions between ambrisentan and warfarin or sildenafil are known to occur.
Phosphodiesterase inhibitors
Phosphodiesterase inhibitors exert their effects via the NO pathway. Nitric oxide has similar vasodilatory, antiproliferative, and antithrombotic effects compared with that of prostacyclin, and its activity is mediated by the intracellular second messenger, cyclic guanosine monophosphate (cGMP). Cyclic guanosine monophosphate leads to pulmonary vasorelaxation; however, it is rapidly degraded by the PDE5 isoenzymes. Phosphodiesterase type 5 inhibition thus acts to enhance cGMP levels and prolong
Sildenafil
Sildenafil, initially approved to treat erectile dysfunction, received FDA approval as a PAH therapy in 2005 based on the findings of the SUPER-1 trial that randomized patients to placebo or sildenafil in doses of 20, 40, and 80 mg 3 times daily for 12 weeks.50 Sildenafil monotherapy in all dosing groups was associated with significant improvement in 6MWD and FC and reduction in mPAP. The current FDA-approved dose is 20 mg 3 times daily based on the SUPER-1 study, showing no significant
Practical management considerations
Sildenafil is rapidly absorbed and has a plasma half-life of approximately 4 hours. Because of its hepatic metabolism, significant drug-drug interactions through the liver Cytochrome P450 (CYP) enzymes have been known to occur. Common side effects with sildenafil include flushing, dyspepsia, visual changes, epistaxis, and headaches, which usually resolve in several weeks with acetaminophen taken before each sildenafil dose.
Tadalafil
Tadalafil, an oral longer acting PDE5 inhibitor, was originally approved for erectile dysfunction by the FDA and for PAH in 2009 at a dose of 40 mg daily. In the PHIRST study that randomized patients with FC II and III PAH to placebo or oral tadalafil at 2.5, 10, 20, or 40 mg daily,59 the tadalafil treated arm experienced a dose-dependent increase in 6MWD. Only the 40-mg dose reached statistical significance for this primary end point, with a similar safety profile to that of lower doses. The
Combination therapy
Although improvements in FC, exercise capacity, and hemodynamics are evident with PAH monotherapy, it is important to bear in mind that none of these treatments independently restore exercise capacity to normal, as the average 12- or 16-week improvement in 6MWD ranges from 30 to 60 m to a final walk distance that is still notably <400 m. Few therapies normalize or lower mPAP by >20%, with the exception of CCBs in vasodilator responders or pulmonary endarterectomy for patients with CTEPH.
Because
Novel therapeutic targets
Pulmonary arterial hypertension drug development continues to target vasconstrictive mechanisms but is now poised to investigate targets of inflammation and angiogenesis. Although many emerging targets have potential in PAH treatment, only a few have been translated from animal study to human trials. Therapeutics aiming to improve NO synthesis include an endothelial NO synthase coupling agent, cicletanine, that is now in phase II development. Endothelial progenitor cells transfected with the
Management of acute RV failure: medical and mechanical options
Unlike LV systolic failure, there are no established algorithms or formal treatment goals for the management of acute RV failure with cardiogenic shock despite its high mortality.73 The management of these critically ill patients is based largely on experience, with each intervention guided by a mixture of physician discretion, inference from physiology, and local practice norms, not randomized investigations.
The main theoretical treatment principle for acute RV failure is maintenance of aortic
Conclusion
Although PAH is an orphan disease with high mortality and for which there is no cure, current treatment strategies have led to considerable gains in the outcomes of these patients. There is still much to learn and accomplish in managing this complex disease. Avoiding delay in diagnosis, referring early or collaborating care with specialized PAH centers, and instituting appropriately tailored drug therapy remain the top priorities for patient care. Given the abundance of clinical trial data in
Disclosures
Richa Agarwal has no disclosures. Actelion, Gilead, Lilly/Icos, Pfizer, Novartis, and United Therapeutics have provided funding to the University of Chicago to support Dr. Gomberg-Maitland's conduct of clinical trials. Dr. Gomberg-Maitland has served as a consultant for Actelion, Gilead, Medtronic, Pfizer, and United Therapeutics.
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